Lessons learned from pre-clinical testing of xenogeneic decellularized esophagi in a rabbit model

Summary Decellularization of esophagi from several species for tissue engineering is well described, but successful implantation in animal models of esophageal replacement has been challenging. The purpose of this study was to assess feasibility and applicability of esophageal replacement using decellularized porcine esophageal scaffolds in a new pre-clinical model. Following surgical replacement in rabbits with a vascularizing muscle flap, we observed successful anastomoses of decellularized scaffolds, cues of early neovascularization, and prevention of luminal collapse by the use of biodegradable stents. However, despite the success of the surgical procedure, the long-term survival was limited by the fragility of the animal model. Our results indicate that transplantation of a decellularized porcine scaffold is possible and vascular flaps may be useful to provide a vascular supply, but long-term outcomes require further pre-clinical testing in a different large animal model

Parameterization Effects in the analysis of AMI Sunyaev-Zel'dovich Observations

Most Sunyaev--Zel'dovich (SZ) and X-ray analyses of galaxy clusters try to constrain the cluster total mass and/or gas mass using parameterised models and assumptions of spherical symmetry and hydrostatic equilibrium. By numerically exploring the probability distributions of the cluster parameters given the simulated interferometric SZ data in the context of Bayesian methods, and assuming a beta-model for the electron number density we investigate the capability of this model and analysis to return the simulated cluster input quantities via three rameterisations. In parameterisation I we assume that the T is an input parameter. We find that parameterisation I can hardly constrain the cluster parameters. We then investigate parameterisations II and III in which fg(r200) replaces temperature as a main variable. In parameterisation II we relate M_T(r200) and T assuming hydrostatic equilibrium. We find that parameterisation II can constrain the cluster physical parameters but the temperature estimate is biased low. In parameterisation III, the virial theorem replaces the hydrostatic equilibrium assumption. We find that parameterisation III results in unbiased estimates of the cluster properties. We generate a second simulated cluster using a generalised NFW (GNFW) pressure profile and analyse it with an entropy based model to take into account the temperature gradient in our analysis and improve the cluster gas density distribution. This model also constrains the cluster physical parameters and the results show a radial decline in the gas temperature as expected. The mean cluster total mass estimates are also within 1 sigma from the simulated cluster true values. However, we find that for at least interferometric SZ analysis in practice at the present time, there is no differences in the AMI visibilities between the two models. This may of course change as the instruments improve.Comment: 19 pages, 13 tables, 24 figure

Detailed SZ study of 19 LoCuSS galaxy clusters: masses and temperatures out to the virial radius

We present 16-GHz AMI SZ observations of 19 clusters with L_X >7x10^37 W (h50=1) selected from the LoCuS survey (0.142<z<0.295) and of A1758b, in the FoV of A1758a. We detect 17 clusters with 5-23sigma peak surface brightnesses. Cluster parameters are obtained using a Bayesian cluster analysis. We fit isothermal beta-models to our data and assume the clusters are virialized (with all the kinetic energy in gas internal energy). Our gas temperature, T_AMI, is derived from AMI SZ data, not from X-ray spectroscopy. Cluster parameters internal to r500 are derived assuming HSE. We find: (i) Different gNFW parameterizations yield significantly different parameter degeneracies. (ii) For h70 = 1, we find the virial radius r200 to be typically 1.6+/-0.1 Mpc and the total mass M_T(r200) typically to be 2.0-2.5xM_T(r500).(iii) Where we have found M_T X-ray (X) and weak-lensing (WL) values in the literature, there is good agreement between WL and AMI estimates (with M_{T,AMI}/M_{T,WL} =1.2^{+0.2}_{-0.3} and =1.0+/-0.1 for r500 and r200, respectively). In comparison, most Suzaku/Chandra estimates are higher than for AMI (with M_{T,X}/M_{T,AMI}=1.7+/-0.2 within r500), particularly for the stronger mergers.(iv) Comparison of T_AMI to T_X sheds light on high X-ray masses: even at large r, T_X can substantially exceed T_AMI in mergers. The use of these higher T_X values will give higher X-ray masses. We stress that large-r T_SZ and T_X data are scarce and must be increased. (v) Despite the paucity of data, there is an indication of a relation between merger activity and SZ ellipticity. (vi) At small radius (but away from any cooling flow) the SZ signal (and T_AMI) is less sensitive to ICM disturbance than the X-ray signal (and T_X) and, even at high r, mergers affect n^2-weighted X-ray data more than n-weighted SZ, implying significant shocking or clumping or both occur even in the outer parts of mergers.Comment: 45 pages, 33 figures, 13 tables Accepted for publication in MNRA

Cell-intrinsic differences between human airway epithelial cells from children and adults

Summary The airway epithelium is a protective barrier that is maintained by the self-renewal and differentiation of basal stem cells. Increasing age is a principle risk factor for chronic lung diseases, but few studies have explored age-related molecular or functional changes in the airway epithelium. We retrieved epithelial biopsies from histologically normal tracheobronchial sites from pediatric and adult donors and compared their cellular composition and gene expression profile (in laser capture-microdissected whole epithelium, fluorescence-activated cell-sorted basal cells and basal cells in cell culture). Histologically, pediatric and adult tracheobronchial epithelium were similar in composition. We observed age-associated changes in RNA sequencing studies, including higher interferon-associated gene expression in pediatric epithelium. In cell culture, pediatric cells had higher colony-formation ability, sustained in vitro growth and out-competed adult cells in a direct competitive proliferation assay. Our results demonstrate cell-intrinsic differences between airway epithelial cells from children and adults in both homeostatic and proliferative states

Study protocol: a multi-centre randomised study of induction chemotherapy followed by capecitabine +/- nelfinavir with high- or standard-dose radiotherapy for locally advanced pancreatic cancer (SCALOP-2)

Background Induction chemotherapy followed by chemoradiation is a treatment option for patients with locally advanced pancreatic cancer (LAPC). However, overall survival is comparable to chemotherapy alone and local progression occurs in nearly half of all patients, suggesting chemoradiation strategies should be optimised. SCALOP-2 is a randomised phase II trial testing the role of radiotherapy dose escalation and/or the addition of the radiosensitiser nelfinavir, following induction chemotherapy of gemcitabine and nab-paclitaxel (GEMABX). A safety run-in phase (stage 1) established the nelfinavir dose to administer with chemoradiation in the randomised phase (stage 2). Methods Patients with locally advanced, inoperable, non-metastatic pancreatic adenocarcinoma receive three cycles of induction GEMABX chemotherapy prior to radiological assessment. Those with stable/responding disease are eligible for further trial treatment. In Stage 1, participants received one further cycle of GEMABX followed by capecitabine-chemoradiation with escalating doses of nelfinavir in a rolling-six design. Stage 2 aims to register 262 and randomise 170 patients with responding/stable disease to one of five arms: capecitabine with high- (arms C + D) or standard-dose (arms A + B) radiotherapy with (arms A + C) or without (arms B + D) nelfinavir, or three more cycles of GEMABX (arm E). Participants allocated to the chemoradiation arms receive another cycle of GEMABX before chemoradiation begins. Co-primary outcomes are 12-month overall survival (radiotherapy dose-escalation question) and progression-free survival (nelfinavir question). Secondary outcomes include toxicity, quality of life, disease response rate, resection rate, treatment compliance, and CA19–9 response. SCALOP-2 incorporates a detailed radiotherapy quality assurance programme. Discussion SCALOP-2 aims to optimise chemoradiation in LAPC and incorporates a modern induction regimen

Risk factors for Coronavirus disease 2019 (Covid-19) death in a population cohort study from the Western Cape province, South Africa

Risk factors for coronavirus disease 2019 (COVID-19) death in sub-Saharan Africa and the effects of human immunodeficiency virus (HIV) and tuberculosis on COVID-19 outcomes are unknown. We conducted a population cohort study using linked data from adults attending public-sector health facilities in the Western Cape, South Africa. We used Cox proportional hazards models, adjusted for age, sex, location, and comorbidities, to examine the associations between HIV, tuberculosis, and COVID-19 death from 1 March to 9 June 2020 among (1) public-sector “active patients” (≥1 visit in the 3 years before March 2020); (2) laboratory-diagnosed COVID-19 cases; and (3) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19, comparing adults living with and without HIV using modeled population estimates.Among 3 460 932 patients (16% living with HIV), 22 308 were diagnosed with COVID-19, of whom 625 died. COVID19 death was associated with male sex, increasing age, diabetes, hypertension, and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR], 2.14; 95% confidence interval [CI], 1.70–2.70), with similar risks across strata of viral loads and immunosuppression. Current and previous diagnoses of tuberculosis were associated with COVID-19 death (aHR, 2.70 [95% CI, 1.81–4.04] and 1.51 [95% CI, 1.18–1.93], respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95% CI, 1.96–2.86); population attributable fraction 8.5% (95% CI, 6.1–11.1)

Western Energy and Land Use Team

no. 8

Global microbialization of coral reefs

Microbialization refers to the observed shift in ecosystem trophic structure towards higher microbial biomass and energy use. On coral reefs, the proximal causes of microbialization are overfishing and eutrophication, both of which facilitate enhanced growth of fleshy algae, conferring a competitive advantage over calcifying corals and coralline algae. The proposed mechanism for this competitive advantage is the DDAM positive feedback loop (dissolved organic carbon (DOC), disease, algae, microorganism), where DOC released by ungrazed fleshy algae supports copiotrophic, potentially pathogenic bacterial communities, ultimately harming corals and maintaining algal competitive dominance. Using an unprecedented data set of >400 samples from 60 coral reef sites, we show that the central DDAM predictions are consistent across three ocean basins. Reef algal cover is positively correlated with lower concentrations of DOC and higher microbial abundances. On turf and fleshy macroalgal-rich reefs, higher relative abundances of copiotrophic microbial taxa were identified. These microbial communities shift their metabolic potential for carbohydrate degradation from the more energy efficient Embden-Meyerhof-Parnas pathway on coral-dominated reefs to the less efficient Entner-Doudoroff and pentose phosphate pathways on algal-dominated reefs. This 'yield-to-power' switch by microorganism directly threatens reefs via increased hypoxia and greater CO2 release from the microbial respiration of DOC